Truncated mutants of the putative Wnt receptor LRP6/Arrow can stabilize beta-catenin independently of Frizzled proteins.
Truncated mutants of the putative Wnt receptor LRP6/Arrow can stabilize beta-catenin independently of Frizzled proteins.
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DOI：
10.1038/sj.onc.1207642
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发表时间：
2004-06-17
期刊：
影响因子：
8
通讯作者：
Brown, AMC
中科院分区：
文献类型：
--
作者：
Brennan, K;Gonzalez-Sancho, JM;Castelo-Soccio, LA;Howe, LR;Brown, AMC
已知Wnt家族的分泌型信号传导蛋白调节多种发育过程，并且它们通过β-连环蛋白的信号传导途径在癌症中经常被激活。Frizzled和LRP 5/6蛋白作为Wnt蛋白的细胞表面受体的组分的鉴定提出了关于它们各自功能的问题。我们已经调查了这个问题，通过卷曲和LRP蛋白的结构功能分析，已牵连在Wnt 1信号。与其他报道一致，我们发现LRP 6/Arrow蛋白的胞外结构域缺失能够激活Wnt/β-catenin信号通路。重要的是，我们的研究结果表明，这种信号从LRP 6/箭头衍生物可以发生在卷曲和配体独立的方式。此外，我们表明，PPSP图案内的LRP 6的细胞内结构域的信号传导所需的。与LRP 6的结果相反，Frizzled蛋白的过表达没有激活该途径。基于配体与Frizzled和LRP 6结合的证据，目前的模型表明这两种蛋白质都是向β-连环蛋白发出信号的Wnt受体复合物的组分。根据这些模型，我们的数据意味着LRP 5/6/Arrow蛋白构成了这些受体的远端信号起始组分。这些结果也支持LRP 5/6是候选癌基因的观点。
Secreted signaling proteins of the Wnt family are known to regulate a diverse range of developmental processes and their signaling pathway through β-catenin is frequently activated in cancer. The identification of both Frizzled and LRP5/6 proteins as components of cell surface receptors for Wnt proteins has raised questions about their individual functions. We have investigated this issue through a structure-function analysis of Frizzled and LRP proteins that have been implicated in Wnt1 signaling. Consistent with other reports, we find that LRP6/Arrow proteins deleted for their extracellular domain are able to activate the Wnt/β-catenin signaling pathway. Importantly, our results demonstrate that this signaling from LRP6/Arrow derivatives can occur in a Frizzled- and ligand-independent manner. Furthermore we show that the PPSP motifs within the intracellular domain of LRP6 are required for signaling. In contrast to results with LRP6, overexpression of Frizzled proteins did not activate the pathway. Based on evidence of ligand binding to both Frizzled and LRP6, current models suggest that both proteins are components of a Wnt receptor complex that signals to β-catenin. In light of these models, our data imply that LRP5/6/Arrow proteins constitute the distal signal initiating component of these receptors. The results also support the notion that LRP5/6 are candidate oncogenes.
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DOI：
10.1111/j.1749-6632.1998.tb10106.x
发表时间：
1998-01-01
期刊：
MORPHOGENESIS: CELLULAR INTERACTIONS
影响因子：
--
作者：
Giarré, M;Semënov, MV;Brown, AMC
通讯作者：
Brown, AMC
DOI：
10.1073/pnas.96.7.3546
发表时间：
1999-03-30
影响因子：
11.1
作者：
Hsieh, JC;Rattner, A;Nathans, J
通讯作者：
Nathans, J
影响因子：
64.8
作者：
Bhanot, P;Brink, M;Nusse, R
通讯作者：
Nusse, R
影响因子：
56.9
作者：
Boutros, M;Mihaly, J;Mlodzik, M
通讯作者：
Mlodzik, M
影响因子：
4
作者：
Huelsken, J;Behrens, J
通讯作者：
Behrens, J